CERTAINHOMOLOGS OF THIOPROCAME
Sept., 1937
[CONTRIBUTION FROM THE CHEMICAL
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LAPORATORY O F SAINT LOUISUNIVERSITY]
Certain Homologs of Thioprocaine' BY CARLF. LISCHER AND CHARLES N. JORDAN Haasen and Fosdick2 reported the synthesis of several alkyl esters of #-aminothiobenzoic acid and of @-diethylamino-ethyl 9-aminothiobenzoate which they named Thiocaine. Karjala and McElvain3 reported the synthesis of 2-methylpiperidinopropylthiol- and -thionbenzoates. All these compounds were reported as efficient tocal anesthetics, so i t was thought that further work an thioprocaine homologs would be interesting. Karjala and McElvain3 prepared their -thiolbenzoates by coupling mercaptans with acid chlorides. Their yields of substituted meraptans were quite low in spite of working in an atmosphere of nitrogen. This method was tried as a means of preparing thioprocaine but was discarded when all attempts to prepare &diethylaminoethyl mercaptan gave the corresponding disulfide. Six dialkyl aminopropyl p-aminobenzoates were prepared essentially according to the method of Hansen and Fosdick p-NO2CeH4COSK + PN02C~HaCOSCHzCHzCHzCl+
pNHzCsH4COSCHzCK2CH,Cl--f P-PJH~CJIICOSCH&H~CHINR These alkamine esters were isolated as their hydrochlorides and were analyzed for chlorine. The analyses indicate with one exception that the compounds were isolated as their dihydrochlorides : y -di-n-butylarninopropyl p-aminothiobenzoate hydrochloride upon analysis gave values for chlorine and sulfur which lie midway between the values calculated for the mono- and dihydrochlorides. Further treatment with dry hydrogen chloride did not alter the analyses, so the compound was believed to be isolated as a mixture of about equal moles of the mono- and the dihydrochlorides. The alkamine ester hydrochlorides were all somewhat hygroscopic, the r-di-allylaminopropy1 and y-di-n-amylaminopropyl p-aminothiobenzoates especially so. Exposure to moist air (1) This article is condensed from a dissertation submitted by Carl F Lirher to the faculty of the Graduate School of S t Louis University in partial fulfilment of the requirements for the degree of Doctor of Philosophy (2) Hansen and Fosdick, THIS JPURNAL, 61, 2872 (1933) (3) Karjala and McElvain, h d , 66, 2966 (1933)
caused the compounds to become bright yellow in color and partially water insolubIe. Preliminary determinations of their local anesthetic action were made by placing sman samples of the hydrochlorides on the tongue and noting the intensity and duration of the anesthetic d e e t . The diethyl-, di-n-propyl- and diisopropylmino derivatives showed mild anesthetic action lasting for ten minutes ; the di-n-amylamino derivative showed somewhat stronger action fasting twenty-five to thirty minutes, while the diallylamino and the di-n-butylamino derivatives showed intense action, lasting €or the former ten to twelve minutes and the latter twenty-five to thirty minutes. I t was noted during the preparation of these compounds that exposure of the tender skin between the fingers or on the back of the hand to wme intermediate products caused the formation of small water blisters which were very sensitive to heat and water. No attempt was made to study the relative vesicant action of these intermediate thio compounds, or whether they all have that action.
Experimental Part I. &p'-Diethylaminodiethyl Disulfide Hydrobromide. -In a round-bottomed flask were placed 200 mi. of ethanol and 9.5 g. of sodium. Excess hydrogen sulfide gas was passed into the sodium ethylate to form sodium hydrosulfide. To this was added 50 g. of l-bromo-2diethylaminoethane hydrobromide4 as the dry salt. After the first reaction had subsided the mixture w a s refluxed for forty-five minutes to complete the reaction. The sodium bromide was filtered from the cooled reaction mixture and the ethanol removed in vacuo a t 50". The residue was distilled in vacuo giving 13.5 g. (53%) of a light yellow, viscous liquid, boiling a t 160' a t 16 mm.; 0.6018 g. dissolved in 22.11 g. of benzene caused a 0.543' lowering of the freezing point from which the molecular weight was calculated a t 256. The theoretical value is 133 for pdiethy laminoethyl mercaptan and 264 for the disulfide, The compound formed a white crystalline hydrobromide melting a t 223' which analyzed for N gave a calculated formula, ClZH30Br2NZs. 11. 7-Chloropropyl pNitrothiobenzoate.-In a roundbottomed flask were placed 48 g. of potassium p-nitrothiobenzoate and 500 ml. of ethanol. Excess l-chloro-3bromopropane was added slowly, the reaction mixture warmed and shaken to start the reaction. The mixture (4) Meyer and Hopff, Ber., 64, 2279 (1921).
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CARLF. LISCHERAND CHARLES N. JORDAN
VOl. 50
TABLE I Compound
I I1 111
IV V VI VI1 VI11
Yield,
%
53 87 90 ~ ~ - N H Z C ~ H ~ C O S C H ~ C H ~ C H ~ N ( C ~ H ~ ) ~ . ~ H C78~ fi-NH2CsH4COSCHL!HL!H2N(CsH?)n.2HCl (n) 60 p-NH~CsH4COSCH2CH2CH2N(CsH~)1.2HCl (iso) 47 fi-NH~CsHL!OSCHzCHnCHzN(CsHs)l.2HCl 38 p-NH2CsH&OSCH2CH2CH2N(C4H9)2*HC1 and 2HC1 56 [(CzH&NCHzCH2 j2S2,2HBr ~~-NOZC~HICOSCHZCHZCH~C~ ~-NHZCBHICOSCHZCH~CH~C~
IX was heated for a n hour on the water-bath to complete the reaction. The ethanol was removed by distillation and the product extracted from the residue with ether. After recrystallization from 95% ethanol the y-chloropropyl pnitrobenzoate formed pale yellow flakes or needles melting a t 59" corr. The yield was 52.1 g. or 87% of the theoretical amount. 111. y-Chloropropyl pAminothiobenzoate.-Eight and four-tenths grams of finely powdered y-chloropropyl p-nitrothiobenzoate was suspended in a previously cooled mixture of 150 ml. of 95% ethanol and 40 ml. of concentrated hydrochloric acid and stirred for twenty hours a t 4" while 10 g. of 100-mesh iron powder was added slowly. The reaction mixture was diluted with four volumes of ice water, neutralized with ammonium hydroxide to a PH of around 6 and extracted with ether. The ether extract was dried over calcium chloride and then treated with dry hydrogen chloride gas to precipitate the hydrochloride. This salt when suspended in water hydrolyzed completely and the free base was extracted with ether and recrystallized from 50% aqueous ethanol, giving white needles melting a t 50-51". The yield was 7.8 g. or 90% of the theoretical amount. IV-IX. y-Diallrylaminopropyl pAminothiobenzoates. -One mole of y-chloropropyl p-aminothiobenzoate and 2.4 moles of dialkylamine were heated in a sealed tube for six hours a t 100". The contents of the tube was washed out with ether and the dialkylamine hydrochloride filtered off. The ether and excess amine were removed in vacuo a t looo, the residue taken up in dry ether and treated (5) Theoretical values for the compound are: monohydrochloride 9.88% C1, 8.98% S; dihydrochloride 18.41% CI,8.32% S; average 14.15% CI,8.62% S.
36
M. p., "C. corn.
223 59-60 50-51 190-191 167 196 143 162 183
Anal tical data Found, Calcd., %
N, C1, C1, C1, C1, C1, C1, CP, S5, C1,
6.52 13.57 15.85 21.21 19.21 19.19 19.21 14.75 8.61 16.66
6.57 13.65 15.80 20.90 19.31 19.31 19.52 16.75
with dry hydrogen chloride. The precipitate formed was treated with water, filtered from insoluble matter, decolorized with charcoal, made basic with ammonium hydroxide and extracted with ether. The ether extract was dried over calcium chloride and treated with dry hydrogen chloride. The hydrochlorides were recrystallized from an ethanol-benzene mixture and gave pale yellow to nearly white crystalline products. These salts were water soluble, although the di-n-butylamino and di-n-amylamino compounds were only slowly soluble in water, first forming a yellow oil which afterward dissolved. The aqueous solutions were fairly stable to boiling, but became cloudy after standing for several weeks. The salts were hygroscopic and the moist salts turned a brilliant yellow, became partially water insoluble, and had a bitter taste and a garliclike odor. Table I gives the yields, melting points, and analytical data obtained for the compounds reported in this paper.
Summary By the method described P,P'-diethylaminodiethyl disulfide and not /3-diethylaminoethyl mercaptan is isolated when 1-bromo-2-diethylaminoethane hydrobromide and sodium hydrosulfide are made to react. Six 7-dialkylaminopropyl esters of p-aminobenzoic acid were prepared and shown to be local anesthetics. ST.LOUIS,MISSOURI RECEIVED JUNE18, 1937
